Regulation of DGAT - dependent lipogenesis in colonic epithelial growth

结肠上皮生长中 DGAT 依赖性脂肪生成的调节

• 批准号: 10598554
• 负责人: Suzana D. Savkovic
• 金额: $ 32.23万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598554
• 关键词: Acyltransferase; Adipose tissue; Attenuated; Automobile Driving; Bioinformatics; Cell Cycle; Cells; Colon; Colonic Neoplasms; Colonic inflammation; Data; Development; Diagnostic; Disease; Disease Outcome; Disease Progression; Environment; Epidemic; Epithelium; Exhibits; FOXO3A gene; Fatty acid glycerol esters; Feedback; Genetic Transcription; Growth; High Fat Diet; Human; Immune; Individual; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-10; Intracellular Accumulation of Lipids; Investigation; Link; Lipase; Lipids; Lipolysis; Mediating; Mediator; Metabolic; Metabolic Pathway; Molecular; Mus; Mutation; Normal tissue morphology; Obese Mice; Obesity; Organelles; Overweight; PIK3CG gene; Pathway interactions; Patients; Pharmacological Treatment; Process; Publishing; Regulation; Signal Transduction; Solid; The Cancer Genome Atlas; Therapeutic; Tissues; Transcript; Triglycerides; Tumor stage; cell growth; cell transformation; colon growth; colon tumorigenesis; diacylglycerol O-acyltransferase; effective therapy; insight; lipid biosynthesis; member; mouse model; novel; obese person; patient population; pharmacologic; prevent; progenitor; transcription factor; transcriptome; tumor; tumorigenesis; tumorigenic

Abstract Obesity is characterized by systemic lipid accumulation, inflammation, and enhanced tumorigenesis in different tissues, including colon. With obesity, intracellular lipid droplets (LDs) are accumulated in fat storing and non-fat storing tissues. These organelles are increased in colonic tumors relative to normal tissues and may be one the explanation for how obesity facilitates colonic tumorigenesis. As obesity is becoming a worldwide epidemic, it is more important than ever to elucidate the tumorigenic processes mediated by LDs dynamics (lipogenesis and lipolysis). This will provide conceptual advances in our understanding of how obesity promotes inflammatory colonic tumorigenesis, and it will drive exploration of critical mechanisms of metabolic reprogramming within tumorigenesis necessary for the development of effective treatment options. We identified a self-reinforcing negative regulatory loop of LDs with the FOXO3 transcription factor involving signaling between transcriptional and metabolic pathways that facilitates colonic inflammation and tumorigenesis. In the proposed project, we will investigate how this regulatory network is reinforced through acyltransferases 1/2 (DGATs) mediated lipogenesis in facilitating tumorigenesis in obesity. Our preliminary data show that DGATs levels are elevated in human and mouse colonic tumors relative to normal (with even higher levels in obese individuals and HFD-obese mice). Elevated DGAT2 transcripts are linked to poor patient survival. This increase in DGATs levels also promotes LDs utilization through adipose triglyceride lipase (ATGL). The expression of DGATs is induced by obesity and inflammatory mediators in colonic cells and is possibly regulated by Myc that is also activated in the colon of FOXO3 deficient and HFD-obese mice. Inhibition of DGATs in human colonic transformed cells blocks the pathway responsible for loss of FOXO3 (PI3K), lowers LDs/ATGL, and attenuates cell growth. We hypothesize that elevated DGATs drive an LD and FOXO3 self-reinforcing loop, blockade of which effectively shuts down this metabolic inflammatory and tumorigenic pathway. Establishing this novel mechanism will have diagnostic and therapeutic significance in colonic tumorigenesis, especially those driven by inflammatory obesity. The proposed project will elucidate DGATs-mediated metabolic mechanisms stimulating colonic cell growth (Aim 1), it will identify the impact of targeting DGATs in attenuating colonic tumorigenesis (driven by mutation and inflammation in HFD-obesity) and the associated remodeling of the immune cell landscape (PMN, MF), molecular pathways (Myc, PI3K), and transcriptome (Aim 2), and it will assess the significance of the DGAT-dependent LD dynamics in human colonic tumorigenesis (advanced, inflammatory, and obesity-associated tumors) of local and TCGA patients (Aim 3). These investigations will provide key mechanistic insights into DGAT-mediated transcriptional and metabolic reprograming in colonic tumorigenesis and establish a solid platform for the development of novel effective pharmacological treatments for colonic inflammation, tumorigenesis, and other HFD-related disorders.

摘要